Five million Americans are presently living with disability as a result of traumatic brain injury (TBI). The majority of TBI research focuses on the factors that influence the onset of pathology, while fewer studies have addressed the mechanisms that promote recovery. Understanding the mechanisms that function to regulate growth and plasticity in the central nervous system (CNS) will provide the fundamental basis for promoting regeneration following TBI. The studies outlined in this proposal will examine a family of molecules, Ephrins and their receptors (Eph receptors), which have been implicated in developmental patterning, axonal guidance and fasciculation, midline development, and synaptic plasticity throughout the developing CNS. We have recently demonstrated that these molecules may also function to regulate growth and plasticity in the injured CNS. We will employ gene-targeted knockout mice to investigate their functions within the precise circuitry of the hippocampus. Aim 1 of this application will investigate their function in regulating mossy fiber axonal growth, dendritic growth, and synaptic plasticity. Aim 2 and Aim 3 will evaluate Ephrin and Eph receptor function following TBI. We will first examine these connections in an established model of mild (3.5 m/s) controlled cortical impact brain injury as they relate to hippocampal dysfunction. We will then examine whether Ephrins and Eph receptors function to mediate regrowth of mossy fiber afferents. These studies will provide essential information on the mechanisms that function to regulate regeneration following TBI, and could lead to therapeutic treatments to promote recovery in the chronically injured patient.